Research

Research

The Chuang lab focuses on structure/function and clinical ramifications of the pyruvate dehydrogenase (PDC) complex and the branched-chain α-ketoacid dehydrogenase (BCKDC) complex and their corresponding regulatory enzymes, i.e. the specific kinases and phosphatases. PDC and BCKDC are highly related mitochondrial protein machines that control the oxidation of glucose and branched-chain amino acids (BCAA), respectively, the latter as a group comprising leucine, isoleucine and valine. Both glucose and BCAA levels are elevated in obesity, type 2 diabetes, heart failure and cancer. Recently, we employed high-throughput screening and structure-based design to develop a new generation of small-molecule inhibitors against pyruvate dehydrogenase kinase isoforms 1-4 (PDKs 1-4) and the single BCKD kinase (BDK). These specific kinase inhibitors are capable of augmenting glucose and branched-chain amino acid (BCAA) fluxes, and show promise in restoring glucose and BCAA homeostasis in rodent models for diabetes/metabolic syndrome and heart failure.